Inhibition of Hsp90: A multitarget approach to radiosensitization

Hsp90, the 90 kDa heat shock protein, is a highly expressed molecular chaperone that modulates the stability and/or transport of a diverse set of critical cellular regulatory proteins. Among Hsp90 clients are a number of proteins, which in a cell type -dependent manner, contribute to tumor cell radioresistance. Exposure of a variety of solid tumor cell lines to clinically relevant Hsp90 inhibitors results in the simultaneous loss of these radioresponse-associated proteins, which is accompanied by an increase in radiosensitivity. This radiosensitization has been linked to a compromise in the DNA damage response to radiation including the inhibition of cell cycle checkpoint activation and DNA double-strand break repair. With respect to potential clinical application, the expression of ErbB3 seems to predict tumor cells that are resistant to the effects of Hsp90 inhibition on radiosensitivity. Moreover, whereas an increase in tumor cell radiosensitivity was consistently reported, the radiosensitivity of normal fibroblasts was not affected by Hsp90 inhibition, suggesting the potential for tumor-selective radiosensitization. This review summarizes the preclinical data available on Hsp90 inhibition and cellular radiosensitivity. Results generated to date suggest that Hsp90 inhibition can provide a multitarget approach to tumor radiosensitization.